Proton and photon radiotherapy in stage III NSCLC: Effects on hematological toxicity and adjuvant immune therapy.

BACKGROUND AND PURPOSE: Concurrent chemo-radiotherapy (CCRT) followed by adjuvant durvalumab is standard-of-care for fit patients with unresectable stage III NSCLC. Intensity modulated proton therapy (IMPT) results in different doses to organs than intensity modulated photon therapy (IMRT). We investigated whether IMPT compared to IMRT reduce hematological toxicity and whether it affects durvalumab treatment. MATERIALS AND METHODS: Prospectively collected series of consecutive patients with stage III NSCLC receiving CCRT between 06.16 and 12.22 (staged with FDG-PET-CT and brain imaging) were retrospectively analyzed. The primary endpoint was the incidence of lymphopenia grade ≥ 3 in IMPT vs IMRT treated patients. RESULTS: 271 patients were enrolled (IMPT: n = 71, IMRT: n = 200) in four centers. All patients received platinum-based chemotherapy. Median age: 66 years, 58 % were male, 36 % had squamous NSCLC. The incidence of lymphopenia grade ≥ 3 during CCRT was 67 % and 47 % in the IMRT and IMPT group, respectively (OR 2.2, 95 % CI: 1.0-4.9, P = 0.03). The incidence of anemia grade ≥ 3 during CCRT was 26 % and 9 % in the IMRT and IMPT group respectively (OR = 4.9, 95 % CI: 1.9-12.6, P = 0.001). IMPT was associated with a lower rate of Performance Status (PS) ≥ 2 at day 21 and 42 after CCRT (13 % vs. 26 %, P = 0.04, and 24 % vs. 39 %, P = 0.02). Patients treated with IMPT had a higher probability of receiving adjuvant durvalumab (74 % vs. 52 %, OR 0.35, 95 % CI: 0.16-0.79, P = 0.01). CONCLUSION: IMPT was associated with a lower incidence of severe lymphopenia and anemia, better PS after CCRT and a higher probability of receiving adjuvant durvalumab.

Adjuvant durvalumab after concurrent chemoradiotherapy for patients with unresectable stage III NSCLC harbouring uncommon genomic alterations.

Adjuvant durvalumab is the standard of care for patients with stage III unresectable non-small cell lung cancer (NSCLC), without progression after concurrent chemo-radiation (CCRT). Patients with stage III NSCLC harbouring epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase rearrangements do not seem to benefit from durvalumab. Data are lacking about patients harbouring other driver genomic alterations (dGA). We performed a multicentre (N = 4, Netherlands and Italy) retrospective study including consecutive patients with unresectable stage III NSCLC and treated with CCRT-with or without adjuvant durvalumab-between 2016 and 2022. We enrolled 271 patients; 130 of which received adjuvant durvalumab. Sixty-six patients had dGA (41 KRAS mutations, 4 EGFR common mutations and 21 uncommon dGA). In the entire population, the median PFS was 24.9 months (95% CI 17.5-32.4) and 12.6 months (95% CI 9.0-16.1) with and without durvalumab (p = 0.001). In the dGA group (excluding common EGFR), mPFS was 12.3 months (95% CI 7.8-16.8) with and 7.6 (95% CI 3.4-11.9) without durvalumab (p = 0.038). For patients with KRAS mutations, mPFS was 12.3 months (95% CI 3.6-20.9) with and 7.2 months (95% CI 1.8-12.6) without durvalumab (p = 0.12). Among patients with uncommon dGA, mPFS was 12.9 months (95% CI 8.4-17.4) with and 7.6 months (95% CI 1.4-14) without durvalumab (p = 0.23). We have shown a meaningful survival benefit of adjuvant durvalumab in patients harbouring KRAS mutations and uncommon dGA. This is the largest stage III NSCLC cohort showing the efficacy of durvalumab in patients with uncommon dGA. Further prospective studies are needed to confirm our results.